title: Circulating CD45+/CD3+ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients.
abstract: Circulating microparticles (cMPs) seem to play important roles in vascular function. Beyond markers of activated cells, cMPs may have potential paracrine functions and influence atherosclerosis. Here, our objective was to characterise a) the abundance and phenotype of cMPs in stable statin-treated heterozygous familial hypercholesterolaemia (FH) patients exposed to life-long hypercholesterolaemia and b) the principal phenotype associated to lipid-rich atherosclerotic plaques in hFH-patients with significant atherosclerotic plaque burden. An age/gender/treatment-matched group of adult-onset non-FH hypercholesterolaemic patients (n=37/group) was comparatively analysed. cMPs were characterised by flow cytometry using annexin-V and cell surface-specific antibodies. Our study shows that LLT-FH patients had higher overall cMP-numbers (p<0.005) than LLT-non-FH patients. Endothelial cell-shed cMPs were also significantly higherin FH (p<0.0005). Within the leukocyte-derived cMP-subpopulations, FH-patients had significantly higher lymphocyte- and monocyte-derived cMP-numbers as well as cMPs carrying leukocyte-activation markers. Normalisation of cMPs by LDL levels did not affect cMP number or phenotype, indicating that the proinflammatory effect was derived from chronic vascular damage. Levels of AV+-total, CD45+-pan-leukocyte and CD45+/CD3+-lymphocyte-derived cMPs were significantly higher in FH-patients with subclinical lipid-rich atherosclerotic plaques than fibrous plaques. Levels of CD45+/CD3+-lymphocyte-MPs above 20,000/ml could differentiate between FH-patients with lipidic or non-lipidic plaques (area under the ROC curve of 0.803, 95%CI: 0.641-0.965, p=0.008). In summary, in this snapshot cross-sectional study cMP concentration and phenotype in FH differed markedly from non-FH hypercholesterolaemia. Patients with life-long high LDL exposure have higher endothelial activation and higher proinflammatory profile, even under current state-of-the-art LLT. cMPs carrying lymphocyte-epitopes appear as markers of lipid-rich atherosclerotic plaques in FH.
authors.forename: Rosa
authors.initials: R
authors.lastname: Suades
authors.forename: Teresa
authors.initials: T
authors.lastname: Padró
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Alonso
authors.forename: José
authors.initials: J
authors.lastname: López-Miranda
authors.forename: Pedro
authors.initials: P
authors.lastname: Mata
authors.affiliation: Prof. Lina Badimon, Cardiovascular Research Center, c/Sant Antoni Mª Claret 167, 08025 Barcelona, Spain, Tel.: +34 935565880, Fax: +34 935565559, E-mail: lbadimon@csic-iccc.org.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000737:chemistry; D050197:Atherosclerosis / Q000097:blood*; D017252:CD3 Complex / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003430:Cross-Sectional Studies; D000939:Epitopes / Q000737:chemistry; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood*; D007249:Inflammation; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008055:Lipids / Q000737:chemistry; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D012372:ROC Curve
chemical_list: D017304:Annexin A5; D017252:CD3 Complex; D000939:Epitopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D017493:Leukocyte Common Antigens
keywords: Atherosclerosis; circulating microparticles; endothelial dysfunction; hypercholesterolaemia; inflammation